Compositions and methods for minimizing or reversing agonist-induced desensitization

ABSTRACT

Methods and compositions are provided for preventing or reversing loss of the therapeutic effect of a drug, where the loss is associated with the repeated administration of the drug to a patient. The method includes administering to the patient a dopamine receptor agonist or partial agonist or a drug that increases the extracellular level of dopamine by enhancing release of dopamine, decreasing the removal of dopamine from the extracellular space, enhancing the synthesis of dopamine within the brain, or decreasing metabolic degradation of dopamine; and also administering to the patient an opioid receptor antagonist in an ultra-low dose amount, wherein the ultra-low dose amount is effective to prevent or reverse loss of therapeutic effects associated with the repeated administration of the drug to the patient. The methods are useful for various treatments, including treating Parkinson&#39;s Disease, Restless Leg Syndrome, depression, schizophrenia, psychostimulant drug abuse, or attention deficit disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/111,455, filed Nov. 5, 2008, which is incorporated by reference inits entirety.

FIELD

This disclosure is generally in the field of pharmaceutical formulationsand drug therapies that involve minimizing or preventing desensitizationof G protein coupled receptors.

BACKGROUND

Opioid antagonists, such as naltrexone and naloxone, are used inrelatively high (i.e., milligram) doses for a variety of treatmentsincluding but not limited to eating disorders, narcotic dependence, andalcoholism. Treatment may involve administering the drug by oral tablet(e.g., REVIA™) or by parenteral injection, at doses in the range of 50mg by tablet daily or 380 mg per month by intramuscular depot. U.S. Pat.No. 6,569,449 to Stinchcomb et al., describes the delivery of a prodrugof the opioid antagonist naltrexone and a transdermal delivery apparatusfor same.

Dopamine is a neurotransmitter, or chemical messenger, that sendsinformation to parts of the brain that control movement, coordination,cognitive functions, and emotions. There are five distinct dopaminereceptors, which differ in terms of their pharmacological profiles andcellular distribution. The D2 receptor and the D3 receptor share manysignaling pathways, are the main targets for most drugs used to treatextrapyramidal movement disorders as well as antipsychotic drugs, andare heavily expressed in the regions of the brain responsible for motorfunctions and emotional functions, respectively. In addition, somestudies have shown that abnormal function of the D2 and D3 receptors areclosely related to schizophrenia. Due to the critical role of these twodopamine receptors in terms of neurological function, many drugs havebeen used that target these receptors to affect dopamine relatedactivity. However, the use of dopamine D2 and/or D3 receptor full andpartial agonists in the treatment of neurological and psychiatricdisorders is limited by desensitization of the dopamine D2 and/or D3receptor induced by repeated use of such drugs, which undesirably canlead to a loss or diminution of therapeutic effects. The diminution intherapeutic effects may lead to the need for higher doses with the riskof untoward side effects. An unwanted loss of effect at the end of thedosing interval, as described by the terms “wearing off” or “on-off”, isthought to be a consequence of change in the constitutive activity of D2and D3 receptors as discussed below.

Drugs which produce higher levels of extracellular dopamine also areused to treat neurological and psychiatric disorders, and cananalogously produce dopamine D2 and/or D3 receptor desensitization.These agents increase extracellular dopamine levels by augmentingdopamine synthesis, by blocking reuptake of extracellular dopamine intodopamine neurons, by releasing dopamine from dopamine neurons, or bydecreasing metabolic degradation of dopamine. Typically, drugs thatincrease extracellular dopamine levels have therapeutic effects whichdecrease with repeated administration or require higher doses of drugs,which may lead to side effects or a loss of the therapeutic propertiesof the drugs earlier in the dosing interval. This diminution or loss oftherapeutic effects is likely related to desensitization of dopamine D2and/or D3 receptors induced by chronic elevation of extracellulardopamine levels.

Parkinson's Disease occurs when a group of cells in the substantia nigrathat produce dopamine begin to malfunction and die. As discussed above,dopamine is a neurotransmitter, or chemical messenger, that sendsinformation to the parts of the brain that control movement andcoordination. When a patient has Parkinson's Disease, hisdopamine-producing cells begin to die, and therefore, the amount ofdopamine produced in the brain decreases. Signals from the brain thattell the body how and when to move are therefore delivered more slowly,leaving a person incapable of initiating and controlling movements in anormal way. The four primary symptoms of Parkinson's Disease are tremor,or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffnessof the limbs and trunk; bradykinesia, or slowness of movement; andpostural instability, or impaired balance and coordination. Othersymptoms may include depression and other emotional changes; difficultyin swallowing, chewing, and speaking; urinary problems or constipation;skin problems; and sleep disruptions.

At present, there is no cure for Parkinson's Disease, but a variety ofmedications provide dramatic relief from the symptoms. Patients areoften given levodopa (L-DOPA, 3,4-dihydroxy-L-phenylalanine)formulations including, but not limited to, combinations of levodopawith carbidopa (SINEMET™). Carbidopa delays the conversion of levodopainto dopamine until it reaches the brain. Nerve cells can use levodopato make dopamine and replenish the brain's dwindling supply. Althoughlevodopa helps many Parkinson's patients, not all symptoms respondequally to the drug. For example, bradykinesia and rigidity typicallyrespond to this drug; however, tremor may only be marginally reduced andproblems with balance and other symptoms may not be alleviated at all.Another typical therapy for Parkinson's Disease is the use ofanticholinergic medications such as benztropine mesylate (COGENTIN™) andbiperiden hydrochloride (AKINETON™) which block nerve impulses to helpimprove muscle control and which decrease levels of acetylcholine inorder to achieve a closer balance with dopamine levels. Anticholinergicmedications may only help control tremor and rigidity and not otherassociated symptoms. Other drugs referred to as dopamimetics including,but not limited to, bromocriptine, pergolide, pramipexole, andropinirole, mimic the role of dopamine in the brain, causing the neuronsto react as they would to dopamine. However, these dopamimetic drugs arenot without undesirable side effects. It would be desirable to developnew or improved therapies for the treatment of Parkinson's Disease.

RLS is a neurological disorder characterized by unpleasant sensations inthe legs and a strong urge to move when at rest in an effort to relievethese feelings. RLS sensations are often described by people as burning,creeping, tugging, or like insects crawling inside the legs. Oftencalled paresthesias (abnormal sensations) or dysesthesias (unpleasantabnormal sensations), the sensations range in severity fromuncomfortable to irritating to painful. Several prescriptionmedications, most of which were developed to treat other diseases, areavailable to reduce the restlessness in the legs. These includemedications for Parkinson's Disease, opioids, muscle relaxants, sleepmedications, and medications for epilepsy.

Medications for Parkinson's Disease are the most common treatment forRLS. These medications include pramipexole (MIRAPEX™), pergolide(PERMAX™), ropinirole (REQUIP™), and a combination of carbidopa andlevodopa (SINEMET™). However, as mentioned above, these medications haveundesirable side effects including abrupt daytime sedation, on-off orwearing off effects, and tolerance requiring higher doses. Higher dosesof the dopamimetics ropinirole and pramipexole have been associated withcompulsive gambling, inappropriate hypersexuality, and drowsiness whichmay occur suddenly during the day, potentially leading to adverseconsequences, such as automobile accidents.

A common problem with the currently available dopamimetic treatments forRLS is tolerance. That is, a medication and dose that has previouslybeen effective for relief of RLS symptoms becomes ineffective, or thesymptoms return earlier. Tolerance leads to the use of higher doses ofthese medications, which increase the probability of unwanted sideeffects.

Major depressive disorder is a condition characterized by a pervasivelow mood and loss of interest or pleasure in usual activities. Themajority of currently used antidepressants target a limited number ofneurotransmitter binding sites or transporters, particularly theserotonin transporter and serotonin receptors including 5HT2A and 5HT1Areceptors, the norepinephrine transporter, the dopamine transporter anddopamine D2 and D3 receptors. Pharmacotherapy based on these agentsfails to produce full remission in at least 30% of patients sufferingmajor depressive episodes. Anhedonia, a global loss of pleasurablefeelings, is a core symptom of depression and is believed to be mediatedby decreased or abnormal dopamine neurotransmission in the limbicsystem, particularly the ventral striatum. A number of studies haveimplicated dysfunction of limbic dopaminergic neurotransmission in theetiology of anhedonia. There remains a significant need for new andimproved antidepressant treatment for patients suffering fromdepression, especially refractory depression.

It also would be desirable to provide new or improved pharmaceuticalformulations and methods for the treatment of symptoms associated withParkinson's Disease, Restless Leg Syndrome, attention deficit disorder,schizophrenia, psychostimulant drug abuse, and other conditions forwhich augmentation of dopamine D2 and/or D3 neurotransmission istherapeutically beneficial that overcome the problems associated withthe currently available treatments. In particular, it would be desirableto provide therapies that minimize or prevent desensitization todopamine augmentation.

It would be desirable to treat Parkinson's Disease, RLS, depression,particularly refractory depression, attention deficit disorder,schizophrenia, and psychostimulant drug abuse by modulating the dopaminesystem, increasing dopamine levels without causing tolerance or on-offeffects. In particular, it would be desirable to prevent tolerance tothe effects of drugs which directly stimulate dopamine D2 and D3receptors or which elevate extracellular dopamine levels by modulatingdopamine D2 and D3 receptor signaling.

SUMMARY

In one aspect, methods are provided for preventing or reversing loss ofthe therapeutic effect of a dopamine receptor agonist or partial agonistassociated with the repeated administration of the dopamine receptoragonist or partial agonist to a patient. In one embodiment, the methodincludes administering to the patient (i) a dopamine receptor agonist orpartial agonist, and (ii) an opioid receptor antagonist in an ultra-lowdose amount, wherein the ultra-low dose amount is effective to preventor reverse loss of therapeutic effects associated with the repeatedadministration of the dopamine receptor agonist or partial agonist tothe patient. The opioid receptor antagonist may be selected, forexample, from naloxone, naltrexone, diprenorphine, etorphine,dihydroetorphine, or a combination thereof.

In another aspect, methods are provided for preventing or reversing lossof the therapeutic effect of a drug associated with the repeatedadministration of the drug to a patient. In one embodiment, the methodincludes administering to the patient (i) a drug that increases theextracellular level of dopamine by enhancing release of dopamine,decreasing the removal of dopamine from the extracellular space,enhancing the synthesis of dopamine within the brain, and/or decreasingits metabolic degradation, and (ii) an opioid receptor antagonist in anultra-low dose amount, wherein the ultra-low dose amount is effective toprevent or reverse loss of therapeutic effects associated with therepeated administration of the drug to the patient.

In still another aspect, pharmaceutical formulations are provided. Inone embodiment, the formulation includes a dopamine receptor agonist orpartial agonist, and an opioid receptor antagonist in an ultra-low doseamount. In another embodiment, the formulation includes an opioidreceptor antagonist in an ultra-low dose amount and a drug thatincreases the extracellular level of dopamine by enhancing release ofdopamine, by decreasing the removal of dopamine from the extracellularspace, by enhancing the synthesis of dopamine within the brain, and/orby decreasing its metabolic degradation in the brain.

In yet another aspect, a method is provided for treating Restless LegSyndrome, Parkinson's Disease, or another dopamine-related movementdisorder in a patient. In one embodiment, the method includesadministering to the patient a dopamine receptor agonist or partialagonist, and administering to the patient an opioid receptor antagonistin an ultra-low dose amount, wherein the dopamine receptor agonist orpartial agonist is administered in an amount that is therapeuticallyeffective when co-administered with the opioid receptor antagonist in anultra-low dose amount.

In a further aspect, methods are provided for treating Parkinson'sDisease in a patient. In one embodiment, the method includesadministering to the patient a dopamine receptor agonist or partialagonist, levodopa, a monoamine oxidase inhibitor, a catechol-O-methyltransferase inhibitor, another drug decreasing the metabolic degradationof dopamine in the brain, or a combination thereof; and administering tothe patient an opioid receptor antagonist in a ultra-low dose amount.

In still another aspect, methods are provided for treating depression ina patient. In one embodiment, the method includes administering to thepatient a therapeutically effective amount of a dopamine agonist, adopamine partial agonist, a dopamine reuptake inhibitor, a monoamineoxidase inhibitor, another drug decreasing the metabolic degradation ofdopamine in the brain, a dopamine releasing drug, a selective serotonindopamine reuptake inhibitor, a serotonin-norepinephrine reuptakeinhibitor, or a serotonin-norepinephrine-dopamine reuptake inhibitor;and administering to the patient an opioid receptor antagonist in aultra-low dose amount effective to prevent receptor desensitization indopamine augmentation and/or to enhance antidepressant or to reducerestlessness.

In another aspect, methods are provide for treating schizophrenia in apatient. In one embodiment, the method includes administering to thepatient a therapeutically effective amount of a partial dopamine agonistor a drug increasing extracellular dopamine levels, and administering tothe patient an opioid receptor antagonist in a ultra-low dose amounteffective to prevent receptor desensitization in dopamine augmentation.

In still another aspect, methods are provided for treatingpsychostimulant abuse in a patient. In one embodiment, the methodincludes administering to the patient a therapeutically effective amountof a dopamine D2 and/or D3 agonist or partial agonist, a dopaminereuptake inhibitor, or a dopamine releasing drug; and administering tothe patient an opioid receptor antagonist in an ultra-low dose amounteffective to prevent receptor desensitization in dopamine augmentation.

In yet another aspect, methods are provided for treating attentiondeficit hyperactivity disorder (ADHD) in a patient. In one embodiment,the method includes administering to the patient a therapeuticallyeffective amount of a drug that increases extracellular dopamine levels,and administering to the patient an opioid receptor antagonist in anultra-low dose amount effective for receptor stabilization.

In a further aspect, methods are provided for treating a dopaminedeficiency disease or condition in a patient. In one embodiment, themethod includes administering to the patient a therapeutically effectiveamount of a dopamine D2 and/or D3 receptor agonist or partial agonist,or a drug increasing extracellular dopamine levels, and administering tothe patient an opioid receptor antagonist in an ultra-low dose amounteffective to prevent or reverse loss of therapeutic effects afterrepeated administration of the dopamine D2 and/or D3 receptor agonist orpartial agonist or drug increasing extracellular dopamine levels.

In another aspect, methods are provided for the treatment of pituitaryadenomas in a patient. In one embodiment, the method includesadministering to the patient a therapeutically effective amount of adopamine D2 agonist, and administering to the patient an opioid receptorantagonist in an ultra-low dose amount effective to reduce or preventdesensitization of dopamine D2 receptors.

In another aspect, treatment methods are provided that includeidentifying a patient having a condition selected from among Parkinson'sDisease, Restless Leg Syndrome, depression, schizophrenia, and/orattention deficit disorder; and administering to the patient an opioidreceptor antagonist in an ultra-low dose amount in combination with anon-opioid therapeutic.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph, illustrating periodic limb movements (legs) insleep index (PLMSI) measured in RLS subjects treated with a clinicallyeffective “full” dosage of pramipexole or ropinirole, a half dosage ofpramipexole or ropinirole, and a half dosage of pramipexole orropinirole in combination with ultra-low dose naltrexone (0.15 μg).

FIG. 2 is a bar graph, illustrating periodic limb movement normalized tothe level seen in Phase 1, i.e. with a half dose treatment ofdopamimetic.

FIG. 3 is bar graph, illustrating the number of PLMs observed in asubject during an initial 3 phase trial and following a one-year trialin which the subject maintained treatment on half dose dopamimetic(pramipexole) plus ultra-low dose naltrexone.

DETAILED DESCRIPTION

Methods are provided to minimize, at least partially reduce, or preventdesensitization of receptors in the situations discussed above,collectively referred to herein as therapeutic dopamine augmentation.Methods are also provided to minimize, at least partially reduce, orprevent desensitization of other G protein coupled receptors (GPCRs)that interact with Filamin A.

In one aspect, methods are provided to prevent desensitization todopamine augmentation by administering a very low dose (ultra-low dose,ULD) of a mu opioid receptor antagonist. As used herein, the terms “muopioid receptor antagonist” and “opioid receptor antagonist” are usedinterchangeably. Opioid receptor antagonists include, but are notlimited to, naltrexone, naloxone, diprenorphine, etorphine, anddihydroetorphine. In preferred embodiments, these methods are used inthe treatment of Parkinson's Disease, Restless Leg Syndrome, depression(e.g., refractory depression), attention deficit disorder,schizophrenia, and psychostimulant drug abuse. In one embodiment, theseindications may be treated by administering to the patient an opioidreceptor antagonist in an ultra-low dose amount in combination with anon-opioid therapeutic agent.

In one aspect, a method is provided for preventing or reversing loss ofthe therapeutic effect, i.e., desensitization, of a drug associated withthe repeated administration of the drug to a patient. The method mayinclude (a) administering to the patient a dopamine D2 and/or D3receptor agonist or partial agonist, or a drug that increases theextracellular level of dopamine by (i) enhancing release of dopamine,(ii) decreasing the removal of dopamine from the extracellular space,(iii) enhancing the synthesis of dopamine within the brain, (iv)decreasing metabolic degradation of dopamine within the brain, or (v) acombination thereof; and (b) administering to the patient an opioidreceptor antagonist in an ultra-low dose amount, wherein the ultra-lowdose amount is effective to prevent or reverse loss of a therapeuticeffect associated with the repeated administration of the drug to thepatient.

In a preferred embodiment, the ultra-low dose of mu opioid receptorantagonist is administered to a patient in combination with adopamimetic medication. Such co-administration of an ultra-low dose muopioid receptor antagonist in dopamine augmentation strategies mayprevent desensitization of the dopamine D2 and/or D3 receptors, allowingthe dopamimetic drug to retain its therapeutic effects at lower doses(minimizing side effects of the dopamimetic) and over longer periodswithout abrupt wearing off.

As used herein, the terms “preventing or reversing”, “preventing orreducing”, “prevent or reverse”, and “prevent or reduce” used indescribing the beneficial effect achieved with administration of the ULDmu opioid receptor include an at least partial reduction and/or an atleast partial reversal of the described receptor desensitization. Theterms include reducing, minimizing, at least partially preventing,and/or at least partially reversing the described receptordesensitization.

As used herein, the term “ultra-low dose” generally refers to dosagesgiven to a patient that are less than 1.5 μg/kg (drug weightdrug/patient weight). For depot injections, however, the ultra-low doseamount may comprise a dosage of about 0.1 ng/kg to 100 μg/kg. In someembodiments, receptor stabilization is achieved by co-administration ofnaltrexone in a dose between about 0.01 ng/kg and about 1.5 μg/kg , andmore preferably between 0.01 ng/kg and about 150 ng/kg in certainembodiments. These dosages may administered one time per day, or 2 to 3times daily. In some embodiments, one or both of the dosages areadministered at night. Other dosing schedules are envisioned. Forexample, the dosages may be administered less frequently in extendedrelease or controlled delivery formulations.

Such co-administration of the opioid antagonist with a dopamine D2 or D3receptor agonist or partial agonist, or with a drug enhancingextracellular dopamine levels, will maintain and prevent loss of thetherapeutic effects of the D2 and/or D3 receptor agonist or partialagonist drugs or the drug enhancing extracellular dopamine levels in thetreatment of neurological and psychiatric disorders including, but notlimited to, Restless Leg Syndrome, Parkinson's Disease, depression,attention deficit disorder, schizophrenia, and psychostimulant drugabuse.

As used herein, the terms “dopamine receptor agonist” and “dopamimetic”are used interchangeably, and refer to a dopamine D2 and/or D3 receptorfull or partial agonist. Examples of dopamine receptor agonists include,but are not limited to, pramipexole, ropinirole, bromocriptine,pergolide, preclamol, talipexole, cabergoline, lisuride, roxindole,rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox, aripiprazole, PD158771, PD128483, N-propylnorapomorphine, apomorphine, sumanirole,aplindore, BP897, CJB090, and RGH237, as well as other dopamine D2and/or D3 agonists and partial agonists known in the art. It isunderstood that the methods described herein may also be used withdopamine receptor agonists which may be synthesized or identified later(e.g., a new chemical entity) using methods known in the art of drugdiscovery.

Agents that increase extracellular dopamine levels by augmentingdopamine synthesis, by blocking reuptake of extracellular dopamine intodopamine neurons, or by releasing dopamine from dopamine neurons,include, but are not limited to, drug formulations containing L-DOPA;amphetamine formulations, including formulations of specificstereoisomers such as d-amphetamine; methylphenidate formulations,including formulations of specific stereoisomers; buproprion; serotonindopamine reuptake inhibitors including but not limited to sertraline;serotonin norepinephrine reuptake inhibitors including but not limitedto duloxetine, venlaxafin or desvenlafaxin, triple reuptake inhibitorssuch as JNJ 7925476, tesofensine, and DOV216303; selectivenorepinephrine reuptake inhibitors such as but not limited toatomoxetine formulations; as well as atypical antipsychotic drugs suchas clozapine, ziprasidone, olanzapine, risperidone, and quetiapine, andthe like. Non-limiting examples of drugs that increase the extracellularconcentration of dopamine by decreasing metabolic degradation ofdopamine include inhibitors of monoamine oxidase and catechol-O-methyltransferase. Examples of such inhibitors include, but are not limitedto, phenelzine, tranylcypromine, selegiline, rasagiline, and tolcapone.

In various embodiments of the treatment methods described herein, theultra-low dose of mu opioid receptor antagonist (or a metabolitetherefor) may be administered to the patient by any of several suitableknown oral or parenteral routes and dosages/delivery forms therefor. Inone embodiment, oral administration may be by a pill, tablet or capsulecontaining a dopamimetic, dopamine reuptake blocker, or dopaminereleasing drug in combination with an ultra low dose opioid antagonist.In one embodiment, the mu opioid receptor antagonist is delivered from adepot formulation for controlled, sustained release. For example, thedepot may include a biodegradable matrix material (which may be ahydrogel) or a suspension of biodegradable polymeric microparticles, inwhich the mu opioid receptor antagonist is encapsulated or otherwisecombined. These depots may be administered, for example, by injection,e.g., subcutaneous or intramuscular injection. Vivatrol (CephalonPharmaceuticals) is an FDA-approved example of this depot technology.

The dopamine receptor agonist or partial agonist, the drug enhancingextracellular dopamine levels, and the mu opioid receptor antagonist maybe referred to herein individually as an “active agent” or collectivelyas the “active agents.”

The dopamine D2 or D3 receptor agonist or partial agonist, or the drugenhancing extracellular dopamine levels, may be administered in the sameor a different dosage form or delivery device, via the same or adifferent delivery route, as the mu opioid receptor antagonist. Thedelivery route may be oral or parenteral. Examples of suitableparenteral routes include topical (transdermal) and transmucosal (e.g.,buccal) administration. The unit dosage form or forms containing one ofactive agents or both active agents may be an oral dosage form orparenteral dosage form. The oral dosage form may be a tablet or capsule.In one case, the active agent(s) may be formulated as a topical cream orgel. In another case, the active agents may be formulated for injection.

In still another case, the active agent(s) may be formulated andcombined with a delivery device known in the art. Examples includedevices for transdermal or subcutaneous administration of the agent(s),such as transdermal patches, microneedle arrays, patch pumps, infusionpumps, or the like. In another example, the device may be an implantabledrug delivery device, such as an osmotic pump, a MEMs pump, or otherpump, or another type of passively or actively controlled releasedevice.

As used herein, the term “patient” includes mammals, such as humans, inneed of medical treatment, including but not limited to the treatment ormanagement of diseases or conditions as described herein. The patientmay be an adult or child.

While the observations, treatment methods, and pharmaceuticalformulations described herein are not bound by any theory, themechanisms described hereinbelow are proposed by which the ultra-lowdose opioid receptor antagonists may exert their effect. Filamin A is anon-muscle, actin-binding, scaffolding protein which is found in thecytoplasm of CNS neurons. Filamin A appears to interact with the thirdintracellular loop of G protein coupled receptors (GPCRs) and to affectthe coupling of these receptors to second messenger systems. GPCRs thatare known to interact with Filamin A include the mu opioid receptor,dopamine D2 and D3 receptors, the calcium sensing receptor, the mGluR4,5, 7 and 8 receptors, the muscarinic M1 receptor, and the calcitoninreceptor.

Filamin A is required for normal receptor trafficking (i.e.externalization and internalization) in cells expressing dopamine D2 orD3 receptors, mu opioid receptors, calcitonin receptors, and other GPCRreceptors that interact with Filamin A. Filamin A, GPCRs and I3-arrestinform a complex required for G protein signaling and internalization ofthese receptors. Ultra-low dose naltrexone has been shown to bind withvery high affinity (4 picomolar) to a pentapeptide segment at thecarboxy terminal of Filamin A which modulates G protein signaling of muopioid receptors. As illustrated in FIG. 2, it is believed that inRestless Leg Syndrome (RLS) the loss of therapeutic effects andaugmentation of symptoms seen following chronic administration ofdopamimetics is due to a loss of dopamine D2/3 receptor signaling withpreservation of dopamine D1 receptor signaling. This is proposed to bedue to differences in receptor internalization and recyclingdistinguishing these dopamine receptors.

With agonist stimulation, dopamine D2/3 receptors are internalized anddegraded due to their interaction with G protein coupledreceptor-associated sorting protein (GASP) leading to degradation ofdopamine D2/3 receptors rather than recycling of these receptors to themembrane surface, which eventually produces prolonged decreases inmembrane externalized dopamine D2/3 receptors. In contrast, dopamine D1receptors which are internalized following dopamine D1 agoniststimulation do not interact with GASP and are efficiently recycled tothe cell surface producing an increase in dopamine D1 versus D2/3signaling.

One mechanism of prevention/reversal of desensitization of dopamine D2/3receptors by ultra low dose naltrexone following chronic administrationof dopamine D2 and D3 agonists could be prevention of internalization ofthese receptors due to the interaction between ultra-low dose naltrexoneand Filamin A affecting the Filamin A, β-arrestin complex required forinternalization. As a possible mechanism, it is proposed that ultra-lowdose naltrexone, naloxone, and similar mu opioid antagonistsco-administered with (a) dopamine D2 and/or dopamine D3 agonists andpartial agonists, (b) a drug increasing synthesis of dopamine, e.g.L-DOPA, (c) a drug releasing dopamine, e.g. amphetamine, (d) a drugblocking reuptake of dopamine, e.g. methylphenidate, or (e) a drugdecreasing the metabolic degradation of dopamine in the brain (e.g.,selegeline) will prevent desensitization of dopamine D2 and/or D3receptors following chronic administration of these drugs. It is furtherproposed that ultra-low doses of naltrexone, naloxone and similar muopioid receptor antagonists will prevent desensitization of the calciumsensing receptor, the mGluR4, 5, 7 and 8 receptors, the muscarinic M1receptor, and the calcitonin receptor following chronic administrationof agonists of partial agonists at these G protein coupled receptors bysimilar mechanisms.

In addition to the prevention of internalization of the above mentionedreceptors, a second possible mechanism for prevention and/or reversal ofdesensitization of these receptors may involve the prevention of aswitch in second messenger signaling from G_(αi) and G_(αo) to G_(s).For example, desensitization of mu opioid receptors has been associatedwith such a switch in G protein second messenger signaling which occurswith repeated administration of opioid agonists. It has been proposedthat binding of ultra-low dose naltrexone and naloxone at thepentapeptide site near the carboxy terminal of Filamin A prevents theopioid induced switch in G protein coupling from G_(αi) to G_(s), andthat prevention of this switch in G protein coupling is a mechanismblocking the desensitization of the mu opioid receptor. The dopamine D3receptor and the muscarinic M1 agonist can signal using G_(αi) or G_(s).The dopamine D2 and mGluR III type receptors, i.e. 4, 6, 7, and 8, alsointeracts with Filamin A and signals through G_(αi) to inhibit adenylcyclase.

It has been proposed that loss of therapeutic effects of dopamimeticsand augmentation of symptom severity with chronic dopamimetic therapy inRLS may be due to a predominance of dopamine D1 signaling relative toD2/3 signaling. In the baseline state, the dopamine D3 and D2 receptorspredominantly signal via G_(60 i) and the net effect of receptoractivation is inhibition of adenyl cyclase. Dopamine D1 receptorstimulation produces stimulation of adenyl cyclase via G_(s) secondmessenger signaling and stimulation of adenyl cyclase.

It is proposed that with continued administration of dopamine D3/D2receptor agonists and/or drugs elevating extracellular dopamine levels,the dopamine D3, and likely the D2, receptor switch G protein signalingfrom predominantly G_(αi) to predominantly G_(s) mediated, resulting inactivation of adenyl cyclase. Such switching produces second messengersignaling effects appearing as desensitization of the dopamine D3, andlikely D2, receptors and apparent dopamine D1 receptor predominance.Such changes in D2/3 second messenger signaling may contribute to lossof therapeutic effects of dopamine D2/3 agonists and partial agonistsand augmentation of symptom severity in subjects with RLS. Similarswitching of G protein coupling is believed to occur in GPCR's thatinteract with Filamin A and signal though G_(αi) inhibit adenyl cyclasewhich it is postulated will be a second mechanism of desensitization ofthese receptors, i.e. muscarinic M1, and mGluR4, 7, and 8 receptors.

In support of a non-opioid mechanism by which ULD mu opioid receptorantagonist affects dopamine desensitization, studies of the effects ofultra-low dose natrexone in a chronic pain model in intact rodents showno effect of ultra-low dose naltrexone in the absence of exogenouslyadministered opioid agonists. Therefore, ultra-low dose naltrexoneappears not to directly affect mu opioid receptor function in theabsence of exogenous opioid agonist administration. The principal effectof ultra low dose naltrexone appears to be a prevention ofdesensitization of the mu opioid receptor only with the administrationof exogenous opioid agonists.

Given the lack of effect of ultra-low dose naltrexone on mu opioidreceptor function in the absence of an opioid agonist, the effects ofultra low dose naltrexone, naloxone and other opioid antagonists whencoadministered with dopamine D2 or D3, muscarinic M1, mGluR4,5,7 or 8,calcium sensing, or calcitonin receptor agonists or partial agonists ismore likely mediated by direct effects on the function of thesereceptors and not to indirect effects resulting from mu opioid mediatedneurotransmission. As a result, these compounds may produce therapeuticeffects in psychiatric and neurological disorders including, but notlimited to, RLS, Parkinson's Disease, depression, attention deficitdisorder, schizophrenia, Alzheimer's Disease, and psychostimulant drugabuse, therapeutic effects that are not attributable to opioid effects.

These actions of ultra-low dose naltrexone, naloxone, and similarcompounds, alone or in combination with the administration of dopamineD2/D3 agonists, or partial agonists or drugs which increaseextracellular dopamine levels offer new and improved therapeuticproperties for the treatment of Restless Leg Syndrome, Parkinson'sDisease, depression, schizophrenia, attention deficit disorder, andpsychostimulant drug abuse and other disorders where dopamineaugmentation is desired.

A. Dopamine-Based Movement Disorders

In one aspect, co-administration of an ultra-low dose opioid receptorantagonist with a dopamine agonist and/or a drug enhancing extracellulardopamine levels may have advantageous effects in the treatment ormanagement of dopamine-based movement disorders such as Restless LegSyndrome and Parkinson's disease.

1. Restless Leg Syndrome (RLS)

Co-administration of an ultra-low dose opioid receptor antagonist with adopamine agonist has advantageous effects in the treatment of RLS. Asdetailed in Example 1, a clear reversal of desensitization ofpramipexole and ropinirole therapeutic effects (i.e., D2 and D3agonists) has been observed in the treatment of RLS when an oralultra-low dose of naltrexone (0.15 μg) was administered along with thesedopamimetics.

For RLS treatment, typical doses of pramipexole and ropinirole are about0.125 mg to about 1.5 mg and 0.25 to 3.0 mg, respectively, taken orallyan hour before sleep. The advantageous effects of co-administration ofnaltrexone (0.15 μg) included earlier onset of action of thedopamimetic, prolongation of therapeutic effects, and an absence of“wearing off” otherwise manifesting as early morning restlessness.

In RLS, chronic treatment with dopamine D2 and D3 agonists can lead tothe need for higher doses to maintain therapeutic effects as well asearly “wearing off” of drug effects manifest as early morningrestlessness. These effects are believed to be due to receptordesensitization. Co-administration of ultra-low dose naltrexone,naloxone, or other opioid receptor antagonist with a dopamine D2 and/orD3 receptor agonist will produce, it is expected, an earlier onset ofaction of the dopamimetic, prolongation of therapeutic effects, and anabsence of “wearing off” otherwise manifesting as early morningrestlessness. Examples of dopamine D2 and/or D3 agonists used to treatRLS include, but are not limited to, pramipexole, ropinirole,bromocriptine, and sumanirole.

In one embodiment, receptor stabilization may be achieved byco-administration of naltrexone, in a dose between about 0.01 ng/kg andabout 1.5 μg/kg with a dopamine D2 and/or D3 receptor agonist, tomaintain and enhance the therapeutic effects of dopamine D2 and/or D3receptor agonist. Naltrexone may more preferably be co-administered in adosage range between 0.01 ng/kg and about 150 ng/kg in certainembodiments. For some patients, the ultra-low dose naltrexone anddopamine receptor agonist may be co-administered in a single dose everynight. For patients experiencing RLS symptoms during the daytime, theultra-low dose naltrexone and dopamine receptor agonist may beco-administered 2 or 3 times daily. Other dosing schedules are possible.

2. Parkinson's Disease

In Parkinson's Disease, dopamine D2 and/or D2/3 agonists, monoamineoxidase inhibitors (MAOi), catechol-O-methyl transferase inhibitors(COMTi), and L-DOPA formulations, either separately or together havebeen shown to be therapeutically efficacious. The dopamine D2 and D2/3agonists include, but are not limited, to pramipexole, ropinirole,bromocriptine, sumanirole, and pergolide. The side effects of “wearingoff” and “on-off” periods, as well as loss of therapeutic efficacy ofthese agents, have been reported with these drugs. These effects arebelieved to be mediated by desensitization of dopamine D2 and D3receptors.

In one embodiment, a treatment method includes co-administration of ULDnaltrexone, naloxone, or other opioid receptor antagonist with adopamine D2 and/or D3 receptor agonist, alone or combination with anL-DOPA formulation, with an L-DOPA formulation plus a COMTi, with anL-DOPA formulation plus an MAOi, or with an L-DOPA formulation plus anMAOi and a COMTi to prevent receptor desensitization. In anotherembodiment, a treatment method includes co-administration of ULDnaltrexone, naloxone, or other opioid receptor antagonist with an L-DOPAformulation, with an L-DOPA formulation plus a COMTi, with an L-DOPAformulation plus an MAOi, or with an L-DOPA formulation plus an MAOi anda COMTi to prevent receptor desensitization. Typical doses of SINEMETused to treat Parkinson's Disease are 1 tablet SINEMET 25/100 TID takenorally or up to 15 tablets SINEMET 25/100 taken orally daily in divideddoses. Typical doses of pramipexole used to treat Parkinson's Diseaserange from 0.125 mg TID orally to 1.5 mg TID orally. The typical dosesof REQUIP used to treat Parkinson's Disease range from 0.25 mg TIDorally to 24 mg per day taken orally in three divided doses. However,escalation of doses with repeated administration of pramipexole andropinirole, which is frequently seen, will be prevented when dopamineaugmenting drugs are co-administered with an ultra-low dose ofnaltrexone, naloxone, or other opioid antagonist.

In one embodiment, receptor stabilization is achieved byco-administration of naltrexone in a dose between about 0.01 ng/kg andabout 1.5 μg/kg with a dopamine D2 and/or D3 receptor agonist,separately or in further combination with an L-DOPA formulation. Instill another embodiment, naltrexone is co-administered in a dosebetween about 0.01 ng/kg and about 1.5 μg/kg with an L-DOPA formulation.In certain embodiments, naltrexone is co-administered in a dosage rangebetween 0.01 ng/kg and about 150 ng/kg. Such co-administration wouldmaintain and enhance the therapeutic effects of the dopamine D2 and/orD3 receptor agonist, the L-DOPA formulation, or both. Compositions andunit dose formulations comprising such active agent combinations may beprovided for the treatment of Parkinson's Disease.

B. Depression, Refractory Depression

Dopamine D2 and/or D3 receptor agonists, as well as drugs increasingextracellular dopamine levels, have been used both separately and inconjunction with other antidepressant drugs to treat unipolar andbipolar depression. Chronic administration of dopamine D2 and/or D3receptor agonists and partial agonists have been shown to producereceptor desensitization, which decreases the therapeutic effects ofthese drugs. Examples of dopamine D2 and/or D3 receptor agonists andpartial agonists and drugs increasing extracellular dopamine levelsinclude, but are not limited to, pramipexole, ropinirole, aripiprazole,sumanirole, methylphenidate formulations (both in immediate and delayedrelease forms, including selective enantiomers), and amphetamineformulations, in both immediate and delayed release form, includingselective enantiomers; bupropion; the serotonin dopamine reuptakeinhibitor sertraline, serotonin norepinephrine reuptake inhibitors suchas duloxetine, venlaxafine or desvenlafaxine, triple uptake inhibitors(serotonin norepinephrine dopamine) such as JNJ 7925476, tesofensine,and DOV 216303, dopamine reuptake inhibitors, as well as drugsdecreasing dopamine metabolism including but not limited to phenelzine,tranylcypromine, selegiline, rasagiline and tolcapone are believed torely, at least partially, on dopamine augmentation as a mechanism fortheir anti-depressant effects.

In one embodiment, treatment methods are provided that includeco-administration of ultra-low dose naltrexone, naloxone, or otheropioid receptor antagonist in combination with (i) a dopamine D2 and/orD3 receptor agonist or partial agonist, (ii) a drug that increasesextracellular dopamine levels, (iii) an MAOi inhibitor (iv) a dopamineand norepinephrine reuptake inhibiting antidepressant, (v) a serotoninand dopamine reuptake inhibiting antidepressant, (vi) a serotoninnorepinephrine reuptake inhibiting antidepressant, (vii) a triple uptake(i.e., serotonin and norepinephrine and dopamine) reuptake inhibitingantidepressant, (viii) a dopamine reuptake inhibiting antidepressant toprevent receptor desensitization, or (ix) a combination of theforegoing. Praximpexole has been used at doses of about 0.125 to about1.5 mg TID taken orally in the treatment of depression. However,co-administration of dopamine augmenting drugs with an ultra-low dose ofnaltrexone, naloxone or other opioid receptor antagonist should preventdose escalation and loss of therapeutic effects. In one embodiment,receptor stabilization is achieved by co-administration of naltrexone ina dose between about 0.01 ng/kg and about 1.5 μg/kg in combination with(i) a dopamine D2 and/or D3 receptor agonist or partial agonist, (ii) adrug that increases extracellular dopamine levels, (iii) an MAOi, (iv) adopamine and norepinephrine reuptake inhibiting antidepressant, (v) aserotonin and dopamine reuptake inhibiting antidepressant, (vi) aserotonin norepinephrine reuptake inhibiting antidepressant, (vii) atriple uptake (i.e. serotonin, norepinephrine, and dopamine) reuptakeinhibiting antidepressant, (viii) a dopamine reuptake inhibitingantidepressant, or (ix) a combination thereof. In certain embodiments,naltrexone is co-administered in a dosage range between 0.01 ng/kg andabout 150 ng/kg. Such treatment may maintain and enhance the therapeuticeffects of dopamine D2 and/or D3 receptor agonists and partial agonists,a drug that increase extracellular dopamine levels, an MAOi, a dopamineand norepinephrine reuptake inhibiting antidepressant, a serotonin anddopamine reuptake inhibiting antidepressant, a serotonin norepinephrinereuptake inhibiting antidepressant, a triple uptake (i.e. serotonin,norepinephrine, and dopamine) reuptake inhibiting antidepressant, or adopamine reuptake inhibiting antidepressant. Compositions and unit doseformulations comprising such active agent combinations may be providedfor the treatment of depression.

C. Schizophrenia

Partial agonists for the dopamine D2 and/or D3 receptors havetherapeutic benefits in schizophrenia and bipolar depression uponinitial treatment, but often demonstrate a loss of efficacy withrepeated administration. These partial agonists include, but are notlimited to, drugs such as preclamol, terguride, talipexole, roxindole,rotigitine, SDZ 208-911, SDZ 208-912, bifeprunox, PD 158771, PD 128483,aripiprazole, aplindore, BP897, and CJB090. A likely mechanism for theobserved loss of efficacy is receptor desensitization. Preclamol hasbeen used in a dose of 300 mg BID taken orally and shown to haveantipsychotic effects; in addition, a dose range of 100 mg to 1,000 mgpreclamol taken orally BID is proposed. Typical doses of aripiprazoleused to treat schizophrenia are from 10 mg to 40 mg per day takenorally. Loss of therapeutic effects with subsequent dose escalationand/or reversal of dose escalation may be achieved when these drugs areco-administered with an ultra-low dose naltrexone, naloxone, or otheropioid receptor antagonist. Drugs that elevate extracellular DA levelshave been shown to produce symptomatic improvements in schizophrenicsubjects with predominantly negative symptoms and to improve cognitionin schizophrenic subjects who are being treated with neuroleptic drugswhich block a sufficient level of DA D2 receptors to control positivesymptoms. These drugs include, but are not limited to, amphetamine andamphetamine formulations, and methylphenidate and methyphenidateformulations.

The co-administration of ultra-low dose naltrexone, naloxone, or otheropioid receptor antagonist, in combination with a dopamine D2/D3 partialagonists, D2 partial agonists, or D3 partial or full agonists may beuseful to prevent dopamine D2 and D3 receptor desensitization. In oneembodiment, receptor stabilization is achieved by co-administration ofnaltrexone in a dose between about 0.01 ng/kg and about 1.5 μg/kg with adopamine D2/3 or D2 partial agonist, or a D3 partial or full agonist. Incertain embodiments, naltrexone is co-administered in a dosage rangebetween 0.01 ng/kg and about 150 ng/kg. Such treatment may maintain andenhance the therapeutic effects of the dopamine D2/3 or D2 partialagonist, or the D3 partial or full agonist, or a drug increasingextracellular dopamine levels. Compositions and unit dose formulationscomprising such active agent combinations may be provided for thetreatment of schizophrenia.

D. Psychostimulant Abuse

Dopamine D2 and/or D3 receptor partial agonists and drugs which increaseextracellular dopamine levels have been shown in animal models ofpsychostimulant abuse to decrease drug rewarded self-administration andreduce the reinforcing and addictive properties of psychostimulantsincluding, but not limited to, cocaine, amphetamine, and amphetaminederivatives such as methamphetamine. However, dopamine D2 and/or D3partial agonists and drugs increasing extracellular dopamine levels canproduce desensitization of dopamine D2 and/or D3 receptors with repeateddosing, limiting the utility of these drugs for extended treatment ofpsychostimulant abuse. In addition, it has been proposed that selectivedopamine D3 full and partial agonists and selective dopamine D2 partialand full agonists will similarly decrease drug rewardedself-administration, reduce the reinforcing and addictive properties ofpsychostimulant drugs, and produce desensitization of dopamine D3 and/orD2 receptors with repeated administration. Full dopamine D2 and D3agonists may be preferentially given via an oral route or by a slowrelease method to allow a gradual rise in brain levels of these drugsthus minimizing the potential subjective effects of full agonists.Examples of these drugs include, but are not limited to, BP897, CJB 090,RGH 237, pramiprexole, ropinirole, preclamol, terguride, aripiprazole,methylphenidate, and amphetamine.

This loss of therapeutic effect seen with desensitization of thedopamine D3 and/or D2 receptor(s) following repeated dosing withdopamine D3 and/or D2 receptor agonists and partial agonists, as well aswith drugs elevating extracellular dopamine levels, are prevented orreversed by co-administration of an ultra-low dose of naltrexone,naloxone, or other opioid receptor antagonist. Selective dopamine D3partial and full agonist compounds are characterized by selective andhigh affinity for dopamine D3 receptors, demonstrate inhibition offorskolin-induced cyclic AMP accumulation, and increase mitogenesis incells expressing the dopamine D3 receptor with an efficacy similar tothat seen with dopamine and other full dopamine D3 agonists. It isexpected that these effects would be selectively reversed in cellsexpressing dopamine D3 receptors by dopamine D3 selective antagonistssuch as nafadotride and similar compounds.

In one embodiment, the dose of methylphenidate used to treatmethamphetamine abuse is 54 mg/day of a slow release methylphenidatepreparation. In accordance with the present disclosure,co-administration of ultra-low dose naltrexone, naloxone, or a similarcompound in combination with a dopamine D3 and/or D2 receptor partial orfull agonist, a dopamine reuptake inhibitor (such as methylphenidate) ora dopamine releasing drug (such as an amphetamine formulation) may beused to prevent dopamine D3 and/or D2 receptor desensitization. In oneembodiment, receptor stabilization is achieved by co-administration ofnaltrexone in a dose between about 0.01 ng/kg and about 1.5 μg/kg with adopamine D3 and/or D2 partial agonist and with drugs which elevateextracellular dopamine levels. In certain embodiments, naltrexone isco-administered in a dosage range between 0.01 ng/kg and about 150ng/kg. Such treatment may prevent the desensitization seen with repeatedadministration, creating a novel composition for the treatment ofpsychostimulant abuse.

E. Attention Deficit Hyperactive Disorder (ADHD)

In another embodiment, the use of an ultra-low dose of naltrexone,naloxone, or other opioid receptor antagonist is provided in combinationwith a drug that enhances dopaminergic neurotransmission by increasingextracellular dopamine levels, for the treatment of attention deficithyperactivity disorder. Decreased phasic dopamine release is believed tobe an important deficit in ADHD. Exemplary agents for coformulationinclude, but are not limited to, a methylphenidate formulation (eitherin immediate or delayed release form, including selective enantiomers),an amphetamine formulation (in either an immediate or delayed releaseform, including selective enantiomers), or a norepinephrine transporterinhibitor such as atomoxetine, all of whose actions are believed to bemediated by augmentation of extracellular dopamine levels, as well asother drugs enhancing dopaminergic neurotransmission.

Typical doses of ADDERALL™, an amphetamine preparation, range from adaily dose of 2.5 mg per day up to doses 30 mg given twice a day orally.Typical doses of CONCERTA™ range from 18 mg/day to 72 mg/day, generallynot to exceed 2 mg/kg/day. Typical doses of RITALIN™ (methylphenidate)tablets are 10 to 60 mg/day given twice or three times per day; higherdoses have been used. Typical doses of atomoxetine are 0.5 mg/kg to 1.4mg/kg taken twice daily orally up to a maximum of a 100 mg daily dose.However, lower doses should be effective, when co-administered with anultra-low dose of naltrexone, naloxone, or other opioid receptorantagonist.

In one embodiment, receptor stabilization is achieved byco-administration of naltrexone in a dose between about 0.01 ng/kg andabout 1.5 μg/kg with a drug which increases extracellular dopaminelevels to treat ADHD. In certain embodiments, naltrexone isco-administered in a dosage range between 0.01 ng/kg and about 150ng/kg. Such treatment may maintain the therapeutic effects of the drugwhich increases extracellular dopamine levels. Compositions and unitdose formulations comprising such active agent combinations may beprovided for the treatment of ADHD.

A distinct benefit of ultra low dose opioid antagonists stabilizingdopamine augmentation in treatment of ADHD would be the prevention ofdose escalation and so allow use of lower doses of agents such asamphetamine salts and methylphenidate, which would minimize the knowncardiovascular risks of arrhythmias, hypertension and and/or tachycardialinked to an elevated lifetime probability of myocardial infarction andstroke.

F. Other Disorders

Other disorders involving dopamine receptors or extracellular dopaminelevels may be treated in accordance with the present disclosure. As withthe specific disorders described herein, other disorders may benefitfrom the use of ultra-low dose naltrexone (or other opioid receptorantagonist) combined with agents that result in agonist or partialagonist actions on dopamine receptors or that increase extracellulardopamine levels. Specifically, prevention of dose escalation due todesensitization of dopamine D2 and/or D3 receptors should allow lowerdoses of these drugs that augment dopaminergic neurotransmission, andthe “wearing off” or “on-off” withdrawal side-effects will bediminished.

In another embodiment, an ultra low dose naltrexone (or other opioidreceptor antagonist) combined a dopamimetic is used in the treatment ofpituitary adenomas. Many pituitary adenomas, including but not limitedto prolactin secreting adenomas, nonfunctioning adenomas, and adenomassecreting ACTH, have membrane expressed dopamine D2 receptors. Agoniststimulation of these receptors inhibits secretion of hormones by suchadenomas, thus decreasing symptoms produced by excessive hormonesecretion from these adenomas. This frequently leads to shrinkage ofadenomas, thereby sparing the patient the need for surgery or radiationtherapy. Such adenomas are treated with dopamine D2 agonists such asbromocriptine, typical doses of 2.5 mg twice daily up to 30 mg daily individed doses, or cabergoline, typical doses of 0.25 mg to 3 mg weekly.Not all such tumors demonstrate an adequate therapeutic response todopamine agonist therapy. The combination of ultra low dose naltrexone(or other opioid receptor antagonist) at 0.01 ng/kg to 1.5 μg/kg orallydaily or depot injection, 0.01 ng/kg to 10 μg/kg, co-administered withsuch dopamine agonist therapy will prevent desensitization of pituitarydopamine D2 receptors, allowing a larger fraction of such tumors to besuccessfully treated and/or to be treated at lower doses of dopamineagonists resulting in lesser treatment related side effects.

In yet another embodiment, an ultra low dose naltrexone (or other opioidreceptor antagonist) combined a dopamimetic is used in the treatment ofobesity and the metabolic syndrome which accompanies obesity includinginsulin resistance and type II diabetes. Studies in humans have shownthat bromocriptine, a dopamimetic, at a dose of 2.5 mg reduces leptin,insulin, and glucose levels in obese female human subjects and improvesglycemic control in type II diabetics. Genetic studies have showngenetic polymorphisms of the dopamine D3 receptor which produce lesserlevels of dopamine D3 signaling are more commonly seen in obese adultsparticularly those with binge eating disorders. Imaging studies havesuggested that decreased dopamine D2 signaling in obese subjects. Animalstudies have shown that bromocriptine administered to leptin deficientanimals reduces hyperphagia and adiposity. Animal studies have shownthat dopamine D2 receptor agonists can ameliorate type II diabeticchanges in obese animals. Ultra low dose naltrexone (or other opioidreceptor antagonist) in combination with dopamine D2 and D3 agonists andpartial agonists including but not limited to bromocriptine will enhancethe metabolic effects of such dopamimetics by preventing desensitizationof dopamine D2 and D3 receptors with chronic treatment.Co-administration of naltrexone in a dose between about 0.01 ng/kg andabout 1.5 μg/kg with a dopamimetic may be used to treat obesity, themetabolic syndrome and type II diabetes. In certain embodiments,naltrexone is co-administered in a dosage range between about 0.010ng/kg and about 150 ng/kg.

In other embodiments, ultra-low doses of mu opioid receptor antagonists,such as naltrexone and naloxone, may be co-administered with agonists ofthe calcium sensing receptor, the mGluR4, 5, 7 and 8 receptors, themuscarinic M1 receptor, or the calcitonin receptor to prevent thedesensitization of the receptors. Co-administration of these agonistswith ultra-low dose opioid antagonists likely will preventdesensitization of those receptors and augment agonist effects for eachof these receptors.

Accordingly, in some embodiments, the ultra-low dose opioid receptorantagonist may be co-administered with agonists or partial agonists orother drugs that directly or indirectly effect the calcitonin receptors,calcium sensing receptors, metabotropic glutamatergic receptors ormuscarinic cholinergic receptors. In certain embodiments, the ultra-lowdose opioid receptor antagonist may be co-administered with drugs thatdirectly or indirectly effect muscarinic receptors, particularly the M1muscarinic receptor. In certain embodiments, the ultra-low dose opioidreceptor antagonist may be administered to prevent or reducedesensitization effects in conjunction with cognitive enhancementtreatments, such as in the treatment of Alzheimer's Disease and to treatcognitive deficits in other disorders such as schizophrenia.

For example, the ultra-low dose opioid receptor antagonist may beco-administered with an M1 muscarinic cholingergic agonist or partialagonist drug or with acetylcholinesterase inhibitors which increase theextracellular levels of acetylcholine in patients with Alzheimer'sDisease and in patients with cognitive impairments due to otherdisorders such as schizophrenia. In Alzheimer's Disease, particularly inmild to moderate Alzheimer's Disease, there is a loss of acetylcholineneurons in brain which is believed to mediate cognitive deficits such asmemory loss. Administration of acetylcholinesterase inhibitors suchgalantamine (Reminyl, Razadyne), donepezil (Aricept), and rivastigmine(Exelon) to subjects with mild to moderate Alzheimer's Disease producesimprovements in cognitive function by increasing extracellularacetylcholine levels. It is believed that M1 muscarinic cholinergicreceptors mediate a substantial part of the cognitive improvement seenwith acetylcholinesterase inhibitors. Typical doses of galantamine areless than 24 mg/day, typical doses of donepezil are 5-10 mg/day, andtypical doses of rivastigmine are 1.5-6.0 mg taken twice daily. Theseimprovements in cognitive function, however, decrease with time. Whilepart of this loss of therapeutic effects may be due to progression ofAlzheimer's Disease, desensitization of the M1 muscarinic cholinergicreceptor with continued use of these medications is believed to mediateanother part of this loss of therapeutic function.

In one embodiment, M1 muscarinic cholingergic receptor stabilization isachieved by co-administration of naltrexone in a dose between about 0.01ng/kg and about 1.5 μg/kg with a drug which increases extracellularacetylcholine levels or with an M1 cholinergic agonist or partialagonist to treat Alzheimer's Disease. In certain embodiments, naltrexoneis co-administered in a dosage range between 0.01 ng/kg and about 150ng/kg. Such treatment may maintain the therapeutic effects of the drugwhich increases extracellular acetylcholine levels. Compositions andunit dose formulations comprising such active agent combinations may beprovided for the treatment of Alzheimer's Disease.

The present methods and compositions can be further understood andillustrated by the following non-limiting examples.

EXAMPLE 1

In an open-label trial, five subjects diagnosed with RLS treated witheither pramipexole or mirapex who had experienced at least one episodeof dose escalation due to loss of therapeutic effects at an initiallytherapeutic dose participated in three phases of testing, with eachphase lasting five nights. PAM-RL ankle monitors (Philips Respironics)were utilized to count Periodic Limb Movements (PLMs), a measurementthat is resistant to placebo effects.

During Phase 1, the subjects were administered 50% the subjects'clinical “full” dosage of pramipexole or ropinirole. In this Phase, anaverage of 19.5 PLMs per hour (range 10.1-32.8) were observed,indicating unsatisfactory treatment of RLS. During Phase 2, the subjectswere co-administered 50% the subject's normal dosage of pramipexole orropinirole along with ultra-low dose naltrexone (0.15 μg). In Phase 2,an average of 9.1 PLMs per hour were observed. During Phase 3, thesubjects were administered 100% the subjects' normal dosage ofpramipexole or ropinirole alone. In Phase 3, an average of 8.5 PLMs wereobserved (range 2.8-17.8) not significantly different from Phase 2. Theresults of the trial are illustrated in FIG. 1.

When PLMs are normalized to the level seen in each subject during Phase1, the results indicate that the addition of 0.15 μg naltrexone to ultralow dose naltrexone lowers PLMs per hour by an average of 53% which ishighly statistically significant even in this small cohort (P=0.006, 2tailed t-test). Full dose pramipexole or ropinirole (Phase 3) produced a63% decrease in PLMs; this was not statistically significantly differentfrom the level of PLMs seen with half dose pramipexole or ropiniroleplus 0.15 μg naltrexone (P=0.07, 2 tailed t-test). The normalizedresults of the test data are illustrated in FIG. 2.

Ultra low dose naltrexone in combination with half the usual dose ofpramipexole or ropinirole therefore advantageously reversed the loss oftherapeutic effects due to desensitization of dopamine D2 and D3receptor signaling seen with chronic dosing.

EXAMPLE 2

One subject of the initial 3 phase trial has now been maintained on halfthe previous dose of pramipexole plus 0.15 μg naltrexone for a year.Monitoring this subject for PLMs for five nights showed no loss oftherapeutic effects, i.e. no evidence of tachyphylaxis, over thisperiod. The subject's PLMSI after 12 months of co-administration therapywas 3.23, indicating an effective treatment of RLS. The subject did notexhibit any evidence of desensitization to the co-administration therapyover the 12 month trial. The results of the initial 3 phase trial andafter 12 month treatment of the co-administration therapy areillustrated in FIG. 3.

Publications cited herein are incorporated by reference. Modificationsand variations of the methods and devices described herein will beobvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

We claim:
 1. A method for preventing or reversing loss of thetherapeutic effect of a dopamine receptor agonist or partial agonistassociated with the repeated administration of the dopamine receptoragonist or partial agonist to a patient comprising: administering to thepatient a dopamine receptor agonist or partial agonist; andadministering to the patient an opioid receptor antagonist in anultra-low dose amount, wherein the ultra-low dose amount is effective toprevent or reverse loss of a therapeutic effect, the loss beingassociated with the repeated administration of the dopamine receptoragonist or partial agonist to the patient.
 2. The method of claim 1,wherein the dopamine receptor agonist or partial agonist is administeredin an amount that is therapeutically effective when co-administered withthe opioid receptor antagonist in an ultra-low dose amount.
 3. Themethod of claim 1, wherein the opioid receptor antagonist is selectedfrom the group consisting of naloxone, naltrexone, diprenorphine,etorphine, dihydroetorphine, and combinations thereof.
 4. The method ofclaim 1, wherein the dopamine receptor agonist or partial agonist isselected from the group consisting of pramipexole, ropinirole,bromocriptine, pergolide, preclamol, talipexole, roxindole, rotigotine,SDZ 208-911, SDZ 208-912, bifeprunox, aripiprazole, PD 158771, PD128483,N-propylnorapomorphine, apomorphine, sumanirole, aplindore, BP897,CJB090, RGH237 and combinations thereof.
 5. The method of claim 1,wherein the ultra-low dose amount of the opioid receptor antagonist isbetween about 0.01 ng/kg and about 1.5 μg/kg.
 6. The method of claim 1,wherein the ultra-low dose amount of the opioid receptor antagonist isbetween about 0.01 ng/kg and about 150 ng/kg.
 7. The method of claim 1,wherein the ultra-low dose opioid receptor antagonist is administeredfrom a device, a composition, or a combination device/composition, whichis separate from a device, a composition, or a combinationdevice/composition for administering the full or partial opioid dopamineagonist.
 8. The method of claim 1, wherein the ultra-low dose opioidreceptor antagonist is administered by depot injection at a dose fromabout 0.01 ng/kg to about 100 μg/kg.
 9. A method for preventing orreversing loss of the therapeutic effect of a drug associated with therepeated administration of the drug to a patient comprising:administering to the patient a drug that increases the extracellularlevel of dopamine by enhancing release of dopamine, decreasing theremoval of dopamine from the extracellular space, decreasing metabolicdegradation of dopamine, or enhancing the synthesis of dopamine withinthe brain; and administering to the patient an opioid receptorantagonist in an ultra-low dose amount, wherein the ultra-low doseamount is effective to prevent or reverse loss of a therapeutic effect,the loss being associated with the repeated administration of the drugto the patient.
 10. The method of claim 9, wherein the drug releasesdopamine from the dopamine neuron, blocks the reuptake of dopamine intothe dopamine neuron by blocking the dopamine transporter, decreases themetabolic degradation of dopamine in the brain, or increases thesynthesis of dopamine, and wherein the drug is administered in atherapeutically effective amount when co-administered with the opioidreceptor antagonist in an ultra-low dose amount.
 11. A pharmaceuticalformulation comprising: a dopamine receptor agonist or partial agonistor a drug that increases the extracellular level of dopamine byenhancing release of dopamine, decreasing the removal of dopamine fromthe extracellular space, decreasing metabolic degradation of dopamine,or enhancing the synthesis of dopamine within the brain; and an opioidreceptor antagonist in an ultra-low dose amount.
 12. The pharmaceuticalformulation of claim 11, wherein the pharmaceutical formulationcomprises at least one unit dosage form.
 13. The pharmaceuticalformulation of claim 11, which comprises a dopamine receptor agonist orpartial agonist, and the dopamine receptor agonist or partial agonist ispresent in an amount that is therapeutically effective whenco-administered with the opioid receptor antagonist in an ultra-low doseamount.
 14. The pharmaceutical formulation of claim 13, wherein thedopamine receptor agonist or partial agonist is selected from the groupconsisting of pramipexole, ropinirole, bromocriptine, pergolide,preclamol, talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912,bifeprunox, aripiprazole, PD 158771, PD128483, N-propylnorapomorphine,apomorphine, sumanirole, aplindore, BP897, CJB090, RGH237, andcombinations thereof.
 15. The pharmaceutical formulation of claim 11,which comprises a drug which increases extracellular dopamine levels andthe drug is present in an amount that is therapeutically effective whenco-administered with the opioid receptor antagonist in an ultra-low doseamount.
 16. The pharmaceutical formulation of claim 15, wherein the drugcomprises L-DOPA, amphetamine, methylphenidate, a monoamine oxidaseinhibitor, a catechol-O-methyl transferase inhibitor, buproprion, aserotonin dopamine reuptake inhibitor, a serotonin norepinephrinereuptake inhibitor, a triple uptake inhibitor, a triple reuptakeinhibitor, a dopamine reuptake inhibitor, or a combination thereof 17.The pharmaceutical formulation of claim 15, wherein the drug comprisessertraline, duloxetine, venlaxafin, desvenlafaxin, JNJ 7925476,tesofensine, DOV216303, atomoxetine, clozapine, ziprasidone, olanzapine,risperidone, quetiapine, phenelzine, tranylcypromine, selegiline,rasagiline, tolcapone, or a combination thereof.
 18. The pharmaceuticalformulation of claim 11, wherein the opioid receptor antagonist isselected from the group consisting of naloxone, naltrexone,diprenorphine, etorphine, dihydroetorphine, and combinations thereof.19. The pharmaceutical formulation of claim 11, wherein the dopaminereceptor agonist or partial agonist, the opioid receptor antagonist, orboth, are in an oral dosage form.
 20. The pharmaceutical formulation ofclaim 11, wherein the ultra-low dose amount of the opioid receptorantagonist is between about 0.01 ng/kg and about 1.5 μg/kg.
 21. Thepharmaceutical formulation of claim 11, wherein the ultra-low doseamount of the opioid receptor antagonist is between about 0.01 ng/kg andabout 150 ng/kg.
 22. The pharmaceutical formulation of claim 11, whereinthe opioid receptor antagonist is selected from the group consisting ofnaloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, andcombinations thereof, and wherein the ultra-low dose amount of theopioid receptor antagonist is between about 0.01 ng/kg and about 1.5μg/kg.
 23. The pharmaceutical formulation of claim 22, which comprises adopamine receptor agonist or partial agonist, and the dopamine receptoragonist or partial agonist is selected from the group consisting ofpramipexole, ropinirole, bromocriptine, pergolide, preclamol,talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox,aripiprazole, PD 158771, PD128483, N-propylnorapomorphine, apomorphine,sumanirole, aplindore, BP897, CJB090, RGH237, and combinations thereof.24. A method for treating Restless Leg Syndrome, Parkinson's Disease, oranother dopamine-related movement disorder in a patient comprising:administering to the patient a dopamine receptor agonist or partialagonist; and administering to the patient an opioid receptor antagonistin an ultra-low dose amount, wherein the dopamine receptor agonist orpartial agonist is administered in an amount that is therapeuticallyeffective when co-administered with the opioid receptor antagonist in anultra-low dose amount.
 25. The method of claim 24, wherein the opioidreceptor antagonist is selected from the group consisting of naloxone,naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinationsthereof.
 26. The method of claim 24, wherein the dopamine receptoragonist or partial agonist is selected from the group consisting ofpramipexole, ropinirole, bromocriptine, pergolide, preclamol,talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox,aripiprazole, PD 158771, PD128483, N-propylnorapomorphine, apomorphine,sumanirole, aplindore, BP897, CJB090, RGH237, and combinations thereof.27. The method of claim 24, wherein the ultra-low dose amount of theopioid receptor antagonist is between about 0.01 ng/kg and about 1.5μg/kg.
 28. The method of claim 24, wherein the ultra-low dose amount ofthe opioid receptor antagonist is between about 0.01 ng/kg and about 150ng/kg.
 29. A method for treating Restless Leg Syndrome (RLS) in apatient comprising: administering to the patient a dopamine receptoragonist or partial agonist; and administering to the patient an opioidreceptor antagonist in an ultra-low dose amount.
 30. The method of claim29, wherein the opioid receptor antagonist is selected from the groupconsisting of naloxone, naltrexone, diprenorphine, etorphine,dihydroetorphine, and combinations thereof
 31. The method of claim 29,wherein the dopamine receptor agonist or partial agonist is selectedfrom the group consisting of pramipexole, ropinirole, bromocriptine,pergolide, preclamol, talipexole, roxindole, rotigotine, SDZ 208-911,SDZ 208-912, bifeprunox, aripiprazole, PD 158771, PD128483,N-propylnorapomorphine, apomorphine, sumanirole, aplindore, BP897,CJB090, RGH237, and combinations thereof.
 32. The method of claim 29,wherein the dopamine receptor agonist or partial agonist comprisespramiprexole or ropinirole.
 33. The method of claim 29, wherein theultra-low dose amount of the opioid receptor antagonist is between about0.01 ng/kg and about 1.5 μg/kg.
 34. The method of claim 29, wherein theultra-low dose amount of the opioid receptor antagonist is between about0.01 ng/kg and about 150 ng/kg.
 35. A method for treating Parkinson'sDisease in a patient comprising: administering to the patient a dopaminereceptor agonist or partial agonist, levodopa, a monoamine oxidaseinhibitor, a catechol-O-methyl transferase inhibitor, or a combinationthereof; and administering to the patient an opioid receptor antagonistin a ultra-low dose amount.
 36. The method of claim 35, wherein theopioid receptor antagonist is selected from the group consisting ofnaloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, andcombinations thereof.
 37. The method of claim 35, wherein the dopamineagonist or partial agonist is selected from the group consisting ofpramipexole, ropinirole, bromocriptine, pergolide, preclamol,talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox,aripiprazole, PD 158771, PD128483, N-propylnorapomorphine, apomorphine,sumanirole, aplindore, BP897, CJB090, RGH237, and combinations thereof.38. The method of claim 35, wherein the ultra-low dose amount of theopioid receptor antagonist is between about 0.01 ng/kg and about 1.5μg/kg.
 39. The method of claim 35, wherein the ultra-low dose amount ofthe opioid receptor antagonist is between about 0.01 ng/kg and about 150ng/kg.
 40. A method for treating depression in a patient comprising:administering to the patient a therapeutically effective amount of adopamine agonist, a dopamine partial agonist, a dopamine reuptakeinhibitor, a monoamine oxidase inhibitor, a dopamine releasing drug, aselective serotonin dopamine reuptake inhibitor, aserotonin-norepinephrine reuptake inhibitor, or aserotonin-norepinephrine-dopamine reuptake inhibitor; administering tothe patient an opioid receptor antagonist in a ultra-low dose amounteffective to prevent or reduce receptor desensitization in dopamineaugmentation.
 41. The method of claim 40, wherein the ultra-low doseamount of the opioid receptor antagonist is between about 0.01 ng/kg andabout 1.5 μg/kg.
 42. The method of claim 40, wherein the ultra-low doseamount of the opioid receptor antagonist is between about 0.01 ng/kg andabout 150 ng/kg.
 43. A method for treating schizophrenia in a patientcomprising: administering to the patient a therapeutically effectiveamount of a partial dopamine agonist or of a drug increasingextracellular dopamine levels; and administering to the patient anopioid receptor antagonist in a ultra-low dose amount effective toprevent or reduce receptor desensitization in dopamine augmentation. 44.The method of claim 43, wherein the ultra-low dose amount of the opioidreceptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 45.The method of claim 43, wherein the ultra-low dose amount of the opioidreceptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 46.A method for treating psychostimulant abuse in a patient comprising:administering to the patient a therapeutically effective amount of adopamine D2 and/or D3 agonist or partial agonist, a dopamine reuptakeinhibitor, or a dopamine releasing drug; and administering to thepatient an opioid receptor antagonist in an ultra-low dose amounteffective to prevent or reduce receptor desensitization in dopamineaugmentation.
 47. The method of claim 46, wherein the ultra-low doseamount of the opioid receptor antagonist is between about 0.01 ng/kg andabout 1.5 μg/kg.
 48. The method of claim 46, wherein the ultra-low doseamount of the opioid receptor antagonist is between about 0.01 ng/kg andabout 150 ng/kg.
 49. A method for treating attention deficithyperactivity disorder (ADHD) in a patient comprising: administering tothe patient a therapeutically effective amount of a drug that increasesextracellular dopamine levels; and administering to the patient anopioid receptor antagonist in an ultra-low dose amount effective forreceptor stabilization.
 50. The method of claim 49, wherein the opioidreceptor antagonist is selected from the group consisting of naloxone,naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinationsthereof.
 51. The method of claim 49, wherein the drug that increasesextracellular dopamine levels is selected from methylphenidateformulations, amphetamine formulations, or norepinephrine transporterinhibitors.
 52. The method of claim 49, wherein the norepinephrinedopamine transporter inhibitor comprises atomoxetine.
 53. The method ofclaim 49, wherein the ultra-low dose amount of the opioid receptorantagonist is between about 0.01 ng/kg and about 1.5 μg/kg.
 54. Themethod of claim 49, wherein the ultra-low dose amount of the opioidreceptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 55.A method for treating a dopamine deficiency disease or condition in apatient comprising: administering to the patient a therapeuticallyeffective amount of a dopamine D2 and/or D3 receptor agonist or partialagonist; and administering to the patient an opioid receptor antagonistin an ultra-low dose amount effective to prevent or reverse loss oftherapeutic effects after repeated administration of the dopamine D2and/or D3 receptor agonist or partial agonist.
 56. The method of claim55, wherein the dopamine deficiency disease or condition is selectedfrom the group consisting of Parkinson's Disease, Restless Leg Syndrome,depression, schizophrenia, attention deficit disorder, andpsychostimulant abuse.
 57. The method of claim 55, wherein the opioidreceptor antagonist is selected from the group consisting of naloxone,naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinationsthereof.
 58. The method of claim 55, wherein the dopamine D2 and/or D3receptor agonist or partial agonist and/or the opioid receptorantagonist is/are administered via a depot injection, a topical cream orgel, a transdermal device, or a pump.
 59. A method for the treatment ofpituitary adenomas in a patient, comprising: administering to thepatient a therapeutically effective amount of a dopamine D2 agonist; andadministering to the patient an opioid receptor antagonist in anultra-low dose amount effective to reduce or prevent desensitization ofdopamine D2 receptors.
 60. The method of claim 59, wherein the dopamineD2 agonist comprises bromocriptine.
 61. The method of claim 59, whereinthe opioid receptor antagonist in an ultra-low dose amount comprisesnaltrexone orally administered in a daily dose of 0.01 ng/kg to 1.5μg/kg.
 62. The method of claim 54, wherein the opioid receptorantagonist in an ultra-low dose amount comprises naltrexone administeredby depot injection of between about 0.01 ng/kg and about 100 μg/kg. 63.A method of treatment comprising: identifying a patient having acondition selected from the group consisting of Parkinson's Disease,Restless Leg Syndrome, depression, schizophrenia, psychostimulant drugabuse, and attention deficit disorder; and administering to the patientan opioid receptor antagonist in an ultra-low dose amount in combinationwith a non-opioid therapeutic agent for the condition.